PROJECT SUMMARY: Cortical motor networks are a critical, if often overlooked, mediator of motor recovery after spinal cord injury (SCI). Cortical networks are required for instructing output through the corticofugal projections to the brainstem and spinal cord, and the plasticity of these networks will be indispensable for re- learning how to use the spinal circuits altered by SCI or therapeutic intervention. Rehabilitation is necessary for both the recovery of corticospinal-dependent forelimb function and the commensurate reorganization of disrupted cortical motor maps. It remains unknown what the underlying circuit mechanisms are that support cortical reorganization after SCI, or whether such broad reorganization is necessary to support functional recovery. The long-term goal is to develop therapeutic interventions that take advantage of cortical plasticity to promote recovery from SCI. The overall objective for this proposal is to identify the intracortical circuitry responsible for restoring skilled forelimb function. The central hypothesis is that latent intracortical connections projecting from de-efferented hindlimb to forelimb areas are required for rehabilitation-mediated recovery of skilled forelimb function after cervical SCI. The rationale for the proposed research is that the knowledge of how the motor cortex incorporates circuit changes after SCI will help us to target new therapies for motor recovery. The following three specific aims are proposed: 1) Record the endogenous activity from intracortical neurons during rehabilitation-mediated recovery from SCI; 2) Determine the structural changes in horizontal connections during rehabilitation from SCI; and 3) Identify the contribution of horizontal connections to motor recovery after SCI. For the first aim, the approach will be to record activity from interconnected hindlimb and forelimb motor regions during skilled forelimb behavior in order to determine their response to rehabilitation from SCI. In the second aim, the approach will be to image structural changes of intracortical axons and dendritic spines in vivo longitudinally during rehabilitation from SCI. In the third aim, the approach will be to 1) silence interconnected neurons in awake, behaving mice to determine their contribution to recovery, and 2) stimulate interconnected neurons and measure forelimb motor evoked potentials. The proposed studies are innovative in that they shift the focus of spinal cord injury research from axon regeneration to the intracortical networks required for interpreting the changes in spinal cord circuitry. The proposed studies are significant because they will provide a detailed understanding of the mechanisms of circuit remodeling that influence recovery. The expectation is that completion of the proposed research will determine the extent to which intracortical neuron plasticity underlies cortical motor map reorganization and supports functional recovery after SCI. These findings will establish a foundation upon which to build therapeutic advances and dictate which strategies are most appropriate to pursue for both acute and chronic SCI.